Dataset Information

MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors.

ABSTRACT: Aberrant expression of myeloid cell leukemia-1 (MCL-1) is a major cause of drug resistance in triple-negative breast cancer (TNBC) cells. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly overexpressed in most TNBC. The present studies show that targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in TNBC cells with silencing or pharmacologic inhibition with GO-203 is associated with downregulation of MCL-1 levels. Targeting MUC1-C suppresses the MEK???ERK and PI3K???AKT pathways, and in turn destabilizes MCL-1. The small molecules ABT-737 and ABT-263 target BCL-2, BCL-XL and BCL-w, but not MCL-1. We show that treatment with ABT-737 increases reactive oxygen species and thereby MUC1-C expression. In this way, MUC1-C is upregulated in TNBC cells resistant to ABT-737 or ABT-263. We also demonstrate that MUC1-C is necessary for the resistance-associated increases in MCL-1 levels. Significantly, combining GO-203 with ABT-737 is synergistic in inhibiting survival of parental and drug resistant TNBC cells. These findings indicate that targeting MUC1-C is a potential strategy for reversing MCL-1-mediated resistance in TNBC.

SUBMITTER: Hiraki M

PROVIDER: S-EPMC4877578 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors.

Hiraki Masayuki M Suzuki Yozo Y Alam Maroof M Hinohara Kunihiko K Hasegawa Masanori M Jin Caining C Kharbanda Surender S Kufe Donald D

Scientific reports 20160524

Aberrant expression of myeloid cell leukemia-1 (MCL-1) is a major cause of drug resistance in triple-negative breast cancer (TNBC) cells. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly overexpressed in most TNBC. The present studies show that targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in TNBC cells with silencing or pharmacologic inhibition with GO-203 is associated with downregulation of MCL-1 levels. Targeting MUC1-C suppresses the MEK → ERK and PI3K → AKT pathw ...[more]

PMID: 27217294

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Project description:BackgroundOxidative stress and cellular senescence (OSCS) have great impacts on the occurrence and progression of triple-negative breast cancer (TNBC). This study was intended to construct a prognostic model based on oxidative stress and cellular senescence related difference expression genes (OSCSRDEGs) for TNBC.MethodsThe Cancer Genome Atlas (TCGA) databases and two Gene Expression Omnibus (GEO) databases were used to identify OSCSRDEGs. The relationship between OSCSRDEGs and immune infiltration was examined using single-sample gene-set enrichment analysis (ssGSEA), ESTIMATE, and the CIBERSORT algorithm. Least absolute shrinkage and selection operator (LASSO) regression analyses, Cox regression and Kaplan-Meier analysis were employed to construct a prognostic model. Receiver operating characteristic (ROC) curves, nomograms, and decision curve analysis (DCA) were used to evaluate the prognostic efficacy. Gene Set Enrichment Analysis (GSEA) Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized to explore the potential functions and mechanism.ResultsA comprehensive analysis identified a total of 27 OSCSRDEGs, out of which 15 genes selected for development of a prognostic model. A high degree of statistical significance was observed for the riskscores derived from this model to accurately predict TNBC Overall survival. The decision curve analysis (DCA) and ROC curve analysis further confirmed the superior accuracy of the OSCSRDEGs prognostic model in predicting efficacy. Notably, the nomogram analysis highlighted that DMD exhibited the highest utility within the model. In comparison between high and low OSCScore groups, the infiltration abundance of immune cells was statistically different in the TCGA-TNBC dataset.ConclusionThese studies have effectively identified four essential OSCSRDEGs (CFI, DMD, NDRG2, and NRP1) and meticulously developed an OSCS-associated prognostic model for individuals diagnosed with TNBC. These discoveries have the potential to significantly contribute to the comprehension of the involvement of OSCS in TNBC.

Dataset Information

MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors.

Publications

MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors.

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